ABSTRACT. Problem. There are distinct sex-based differences that affect the natural history of HIV infection and HIV- specific immune responses. These differences are partially driven by sex hormones (estrogens in particular) and might influence the size, distribution and transcriptional activity of the HIV reservoirs. Unfortunately, cis- gender women represent only 11% of all participants recruited to HIV cure research and there is a significant knowledge gap between the biology of HIV cure in men and women. Even less is known about the effect of exogenous sex hormones on the viral reservoir and immune response in HIV-infected transgender women. What we know now. One study including >500 HIV-infected participants on antiretroviral therapy (ART) found that women have on average significantly lower levels of HIV DNA in peripheral mononuclear blood cells (PBMC) than men. Various in vitro studies reported sex-based differences on HIV infection and replication in target cells. These differences are partially driven by estrogens that inhibit HIV transcription, through estrogen receptor-dependent mechanisms. Our proposed solution. We will prospectively enroll 15 HIV-infected transgender women (?male-to-female?) on ART with suppressed HIV RNA for >12 months, who plan to start estradiol-based hormonal therapy (HT). We will follow this cohort for 12 months. We will collect longitudinal blood samples before and after initiation of HT. We are uniquely positioned to recruit this ?hard-to-reach? population thanks to our collaboration with ?The Night Clinic? in San Diego, which is following >400 unique transgender women, 40% of whom are HIV-positive. Our goal. We will characterised extensively the HIV reservoir and generate immunological data at each time- point. We will use these data to determine the effect of sex hormones and receptor expression (in particular estradiol) on the HIV reservoir size and transcriptional activity over 12 months of follow-up while on suppressive ART. Historical data from a similar cohort of HIV-infected men (matched by baseline HIV DNA levels, age, CD4+ cells, time on ART and duration of HIV infection) will be used as a comparison. How will we advance the field. Transgender women are disproportionately impacted by HIV in the United States and worldwide and face overwhelming disparities. There is urgent need to include transgender women in the HIV cure agenda, and to adapt curative approaches to meet the unique needs of this specific population. Investigating the effect of estradiol-based HT on the HIV reservoir size and transcriptional activity in transgender women will provide the unique opportunity to the isolate the effect of estradiol on HIV transcription.